The ultimate opportunity presented by discovering the genetic basis of human heart disease is accurate prediction and prevention of disease. By identifying at-risk individuals prior to clinical diagnosis and developing novel therapies to delay or prevent phenotypic expression, genetic discoveries can change medicine. Hypertrophic cardiomyopathy (HOM) provides a paradigm for realizing this opportunity. HOM is caused by sarcomere gene mutations and is the most common genetic cardiovascular disorder. It is characterized clinically by left ventricular hypertrophy (LVH), diastolic dysfunction, and increased risk for arrhythmias, sudden death, and heart failure, and histopathologically by myocyte hypertrophy, disarray and fibrosis. Disease typically presents late in adolescence and symptoms are progressive. The contemporary clinical diagnosis of HOM rests on finding unexplained LVH on cardiac imaging. However this binary metric only defines established disease and fails to capture earlier phenotypes caused by mutations. In contrast, using genetic testing, we can identify individuals with a pathogenic sarcomere mutation (genotype (G)+) at high risk for developing disease before the emergence of overt clinical manifestations (LVH-). Our investigations of G+/LVH- subjects have defined novel markers of early disease in this important new subset, denoted preclinical H(3M. Studying preclinical HCM allows further identification of early phenotype, and surrogate endpoints of treatment response, as well as initiation of therapy to prevent disease onset. We have identified promising new treatment modalities that mitigate the development of HCM in animal models through modification of intracellular calcium handling using diltiazem, and through TGF-beta inhibition using losartan. Importantly, treatment administered after LVH was established was ineffective in reversing histopathology. Together these data indicate that we have a unique opportunity to identify genetic risk and intervene early in HCM. The proposed studies in this Stage 1 planning application will fulfill the prerequisites for effective translation to human clinical trials. We will establish a HCM clinical network for comprehensive study of preclinical disease, identification of subjects, and definition of surrogate endpoints of treatment response. These efforts will culminate in a Stage 2 clinical trial to test a novel strategy of disease prediction and prevention in HCM to decrease symptoms, sudden death, and heart failure. RELEVANCE (See instructions): Hypertrophic cardiomyopathy (HCM) is the most common cardiovascular genetic disorder and associated with an increased risk of sudden death and heart failure. Basic investigation has defined the genetic etiology, elucidated disease mechanisms, and identified strategies to prevent disease. Clinical translation is now possible, reshaping medicine by using genetics to identify at-risk patients and initiate early therapy.